ProjectSummary/Abstract Celiacdisease(CD)isanautoimmunedisorderofthesmallintestine,afflictingabout1%oftheworld's population, for which there is no cure. Currently the only therapeutic option to avoid gastrointestinal? related symptoms and potentially long?term health consequences is the life?long strict adherence to a glu? ten?freediet(GFD).However,amajorityofpatientsneverfullyrecover.Thereisahugeunmetneedfora therapeuticsolutiontobeusedasanadjuncttoaGFD.Thereisafurtherunmetneedforaneffectiveand minimally?invasive tool to monitor small intestinal recovery in CD patients as an alternative to esoph? agogastroduodenoscopy(EGD),whichisinvasive,costlyandnotgenerallyrecommendedbycliniciansfor diseasemonitoring. ImmunogenX is a clinical?stage therapeutic and diagnostic company focused on celiac disease (CD). Ourleadproductdevelopmentistheorallyadministeredenzymeproductlatiglutenase,whichhasshown evidenceforhistologicprotectionandsymptomreductioninresponsetoexposuretomoderateamountsof dietary gluten. The mechanism of action is the proteolytic digestion along specific glutamine and proline bonds of digestively resistant gluten peptides in the stomach using a combination of two digestive en? zymes.OurdiagnosticproductCypCelisbasedonadrugbiomarkersimvastatin(SV)thatishighlyme? tabolizedinthesmallintestineandispresentinbloodatconcentrationsthatareproportionaltotheextent ofvilloushealth. Latiglutenase, a two?enzyme natural product, has a strong scientific premise to justify further clinical testing.Ithasbeenshowninavarietyofmodelstomachexperimentstodetoxifyantigenicglutenproteins. Furthermore,therehasbeensufficientanimalandhumansafetydatatoberegisteredasadietarysupple? ment.However,wewouldfirstliketoobtainmorescientificdatatoinformusonthemostresponsibleand optimalpathtowardfurtherdevelopmentandproductlaunch.Previousclinicaltrialshaveyieldedencour? agingbutinconclusiveinformationregardingitsimpactonimprovingmucosalhealth.Weproposetothe NCCIHastudytofillthisgapinourscientificknowledge. In this application we propose a human study consisting of a gluten?challenge for diagnosed CD pa? tientsinremission.Wewillemployplaceboandlatiglutenasearmsina1:1ratioandwillmeasurethebio? logicalsignaturesformucosalchangesusingbiopsyreadingsofvillousheighttocryptdepthratio(Vh:Cd) andCypCelmeasurements(asaminimally?invasiveindicatorofmucosalhealth).Thetrialwillbepowered toaprimaryendpointforbiopsyVh:CdandsecondaryendpointforSVlevelinserumsamplescollected1 and 2 hours after administration. Our enrollment target based on adequate powering of the primary and secondary endpoints is 40 completed patients. We will also employ the recently validated Celiac Disease ? SymptomDiarypatientreportedoutcome(CDSD PRO)toolforCDsymptomsinordertodemonstratean associationbetweenthechangeinthebiologicalsignature(Vh:Cd)andimprovementinaclinicaloutcome (symptoms).WeanticipatecompletingthisenrollmentattheMayoClinic(Rochester,MN)wherewehave already initiated a CypCel trial. This work will provide vital scientific data to help justify further clinical testing. 1